The present invention relates to 1,2-disubstituted ethyl amides useful in the treatment and prevention of atherosclerosis.
Atherosclerotic coronary heart disease represents the major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male sex, cigarette smoking and serum cholesterol. A total cholesterol level in excess of 225-250 mg/dl is associated with significant elevation of risk.
Cholesterol esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Formation of cholesterol esters is also a key step in the intestinal absorption of dietary cholesterol. The intracellular esterification of cholesterol is catalyzed by the enzyme acyl CoA:cholesterol acyl transferase (ACAT, EC 2.3.1.26). Thus, inhibition of ACAT is likely to inhibit the progression of atherosclerotic lesion formation, decrease the accumulation of cholesterol esters in the arterial wall, and block the intestinal absorption of dietary cholesterol.
A number of amides have been reported as being useful in lowering cholesterol and/or in inhibiting the formation of cholesterol-containing lesions in mammalian arterial walls. U.S. Pat. No. 3,784,577 to Fukurmaru et al discloses fatty acid amide derivatives of the formula R--CONHR.sup.1 wherein RCO is a fatty acid radical and R.sup.1 is 1-.alpha.-benzylbenzyl.
U.S. Pat. No. 4,603,145 to De Vries et al discloses diaryl alkanamides of the formula ##STR2## wherein R.sup.3 and R.sup.4 independently include benzyl and phenethyl.
U.S. Pat. No. 4,420,475 to Damon et al discloses silicon-bearing amides of the formula ##STR3## wherein R.sup.1, R.sup.2 and R.sup.3 independently can be alkyl, phenyl, benzyl or phenethyl and R can be 1-.alpha.-benzylbenzyl optionally substituted in the phenyl rings. U.S. Pat. No. 4,434,161 to Barcza discloses similar compounds having a sulfur atom in the chain between the silicon atom and the carbonyl group.
U.S. Pat. No. 4,456,619 to Kathawala discloses amides of 2-alkynoic acids of the formula ##STR4## wherein A is alkyl, alkenyl or cyclopropanyl-substituted alkyl and B can be 1-.alpha.-benzylbenzyl, optionally substituted in the phenyl rings.
U.S. Pat. No. 4,716,175 to Hoefle et al discloses fatty acid amides of the formula ##STR5## wherein A is an alkyl chain, R.sup.1 and R.sup.2 can each be phenylmethyl, and B can be phenyl, benzyl, pyrimidinyl or pyridyl.
U.S. Pat. No. 4,518,789 to Yu et al discloses dermatologically useful phenyl alpha-acyloxyacetamides of the formula ##STR6## wherein R.sup.1 and R.sup.2 can be hydrogen, alkyl or aralkyl and R.sup.3 and R.sup.4 can be hydrogen, alkyl, aralkyl or aryl.
While some of these diphenylethylamides have shown in vitro ACAT inhibitory activity, none have been reported to show significant activity in whole animal models of atherosclerosis.